U.S. Pat. No. 5,280,040 discloses a class of 3,4-diarylchromans and their salts useful in the treatment of bone loss. Furthermore, PCT/DK96/00014 discloses that these compounds are useful in the treatment of hyperlipoproteinaemia, hypertriglyceridaemia, hyperlipidaemia, or hypercholesterolaemia or arteriosclerosis or for anticoagulative treatment. PCT/DK96/00015 discloses that these compounds are useful in the treatment of gynaecological disorders, such as endometriosis, dysfunctional bleedings, endometrial cancer, polycystic ovarian syndrome and anovulatoric bleeding and for the induction of endometrial thinning. The compounds are also known to have useful effects on gynaecomastia, obesity, vasodilation (respectively from PCT/DK96/00012, PCT/DK96/00011, and PCT/DK96/00013) and furthermore on e.g. Alzheimers disease (PCT/DK96/00010).
A process for the preparation of (+,-)-3,4-trans diarylchromanes is described in U.S. Pat. No. 3,822,287 and by Suprabhat Ray et al. in J.Med.Chem.19,276 (1976). The (+,-)-3,4-trans-isomer is obtained by conversion of the (+,-)-3,4-cis-isomer by means of an organometallic base-catalyzed rearrangement as described in U.S. Pat. No. 3,822,287.
The resolvation of (+,-)-3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)e thoxy]phenyl}chromane in its optical antipodes is described in U.S. Pat. No. 4,447,622. According to this process the (+,-)-3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)e thoxy]phenyl}chromane is reacted with di-p-toluoyl-l-tartaric acid monohydrate in a protic solvent, the reaction mixture is subjected to fractional crystallization and the crystalline salt is subjected to alkaline hydrolysis to produce the desired enantiomer.
Example 1 of U.S. Pat. No. 4,447,622 describes the preparation of the (-)-3,4-trans enantiomer, shown by the following formula: ##STR1##
When using the process disclosed in U.S. Pat. No. 4,447,622 the desired (-)-3,4-trans enantiomer is only obtained with a low chiral purity, less than 80% ee (enantiomeric excess) after the first crystallization. In order to improve the chiral purity the enantiomer has to be crystallized several times.
One object of the present invention is therefore to provide a new process involving an enzymatic resolution step for the preparation of (-)-3,4-trans enantiomers of compounds of formula I which process is adaptable to large scale manufacture, provide good yields and high purity and reduce the cost of manufacture.